Among drug dependence disorders, nicotine dependence is the most widely diffused, with a strong impact on the world's health and economy. The tobacco epidemic is a global problem; one-third of the worldwide population over 15 years of age or 1.1 billion people smoke. By the year 2025, the WHO estimates there will be 10 million tobaccorelated deaths per year worldwide. Smoking cessation treatment is highly cost-effective, and pharmacotherapy is universally recommended for treatment of nicotine dependence in the absence of specific contraindications. However, the majority of smokers do not quit even with treatment. Currently available treatments do not exploit recent advances inknowledge of neurobiologic mechanisms of addiction and reward that have made possible the development of rationally designed treatments targeting specifically those systems involved in nicotine reward circuitry. Existing and new pharmacotherapies along with prevention efforts are key to improving smoking cessation rates and reducing the premature and preventable morbidity and mortality associated with tobacco use. This RFA has prompted three organizations with longstanding interest in pharmacotherapy for nicotine dependence, Massachusetts General Hospital (MGH), McLean Hospital Brain Imaging Center (BIC), and GlaxoSmithKline (GSK), to join forces for the proposed NCDDG-MD/NA Group. The primary objective of this group is to identify and test promising compounds that affect critical neural systems in nicotine reward and craving. In this collaborative group project for drug discovery, we will combine screening of multiple potential lead compounds, with pre-clinical and clinical testing of two compounds and in vivo brain imaging measures. Specifically, we will 1) screen multiple lead compounds in neurochemistry, electrophysiology, behavioral and animal brain imaging assays, 2) screen multiple promising compounds identified in the preclinical work in a novel human 72 hour nicotine craving paradigm, 3) perform clinical trials to test the efficacy of the most promising two compounds for smoking cessation, compared with placebo and bupropion and 4) use in vivo neuroimaging to identify surrogate markers for treatment response and relapse in humans. This effort will advance our understanding of mechanisms involved in nicotine dependence, early abstinence/treatment response and relapse, will advance our understanding of what types of agents are effective in treating nicotine dependence, will test a battery of putative surrogate markers for clinical response aimed at accelerating the process by which effective drugs can be assessed for efficacy in nicotine dependence and will test two compounds for nicotine dependence in adequately powered trials. The compounds that we will investigate will be drawn from the large, existing portfolio of compounds under development for nicotine dependence at GSK. Each organization will make a unique contribution of personnel and resources to the implementation and success of the project.